V. A. Anisimova

Synthesis and Pharmacological Activity of 1-n- and 10-n-substituted 1(10),2,3,4-tetrahydropyrimido-[1,2-a]benzimidazoles

Earlier, Kochergin [5] proposed a method for the synthesis of 2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazoles based on the interaction of 1-ethyl-2-aminobenzimidazoles with 1,3-bromochloropropane in toluene. However, this pathway is ineffective in obtaining compounds Ia – Id because half of the initial amine IIIa – IIId is spent for binding a hydrogen halide evolved during the reaction, so that the target product yield does not exceed 45 – 50%. Better results can be obtained using a method proposed in our previous study [6] for the synthesis of 10-benzyland 10-phenyl-substituted tricyclic derivatives, which is based on the intramolecular cyclization of 2-chloropropylaminobenzimidazoles (VIIa – VIId) prepared from readily accessible benzimidazole-2-sulfonic acids (Va – Vd) [7].

Synthesis and Pharmacological Activity of 2-Methoxyphenyl-Substituted 9-Dialkylaminoethylimidazo[1,2-a]benzimidazoles

A series of 2-methoxyphenyl-9-dialkylaminoethyl derivatives of imidazo[1,2-a]benzimidazole have been synthesized and their pharmacological properties have been studied. Some of the synthesized compounds exhibit antioxidant, radioprotector, antiarrythmic, spasmolytic, antiaggregant, anticalmodulin, and antisecretory properties. Some substances exhibit the properties of phosphodiesterase inhibitors, decrease calcium ion transport through membranes, increase myocardium resistance to hypoxia, and reduce the arterial pressure. The obtained data show good prospects for the synthesis and screening of biologically active substances in this chemical group.

Synthesis and pharmacological activity of 3-(2,2,2-trichloro-1-hydroxyethyl)imidazo [1, 2-a]benzimidazole dihydrochlorides

Aseries of 3-(2,2,2-trichloro-1-hydroxyethyl)imidazo[1, 2-a]benzimidazole dihydrochlorides have been synthesized and their pharmacological properties have been studied. It is established that the synthesized compounds exhibit weak antioxidant activity. In addition, they possess platelet and erythrocyte antiaggregant properties, show pronounced spasmolytic action, and have low toxicity. Some of them also exhibit antiradiomimetic, hypotensive, and antiarrhythmic properties.

Synthesis and Pharmacological Activity of 2-(Hetaryl)imidazo[1,2-a]benzimidazoles

2,9-Disubstituted imidazo[1,2-a]benzimidazoles were reported to have a pharmacological effect on the cardiovascular system [1, 2], blood [3, 4], and gastrointestinal tract [5, 6]. However, derivatives with hetaryl substituents have been insufficiently studied in this respect: to our knowledge, only one such compound, 2-(nitrothienyl)imidazo[1,2-a]benzimidazole, was synthesized by Indian researchers with a yield of 25% [7]. At the same time, it is known that the introduction of hetaryl substituents into condensed systems with common nitrogen atoms can significantly modify the biological activity of the initial compounds (see, e.g., [8 – 10]). We have successfully introduced various hetaryl radicals ( -excessive thienyl, furyl, and -deficient 1-methylbenzimidazol-2-yl [11]) into position 2 of the imidazo[1,2-a]benzimidazole nucleus and studied the pharmacological properties of the synthesized compounds. A series of 2-(hetaryl)imidazo[1,2-a]benzimidazoles (V – VIII) was synthesized using a method based on the condensation of 1-R-2-aminobenzimidazoles with hetarylbromomethylketones, followed by cyclization of the resulting 2-amino-3-hetaroylmethylbenzimidazolium bromides (I – IV) (cf. [12, 13]). The reaction of quaternization of 1-R-2-aminobenzimidazoles with bromoketones proceeds smoothly in acetone with a quaternary salt yield from 81 to 98% (Table 1). The IR spectra of salts I – IV (measured in Vaseline oil) contain the characteristic absorption bands due to carbonyl groups (1705 – 1710 cm – 1 for compound I and 1670 – 1680 cm – 1 for II – IV) and two bands related to the stretching vibrations of primary amino groups (3150 – 3350 cm – ), which indicates that these compounds can exist in the crystalline state in the form of 2-aminobenzimidazolium salts. The H NMR spectra of the bromides I – IV exhibit two-proton singlet signals ( = 5.90 – 5.95 ppm) corresponding to methylene protons of the hetaroylmethyl radicals. The signals from protons of the amino group appear as narrow 2H-singlets at = 8.95 – 9.00 ppm. These signals are absent in the H NMR spectra of the target tricyclic bases V – VIII.

Synthesis and pharmacological activity of aroylmethyl derivatives of tricyclic benzimidazole systems containing hydroxy groups in aroyl radicals

The synthesis and pharmacological properties of a series of aroylmethyl derivatives of tricyclic benzimidazole systems containing hydroxy groups in aroyl radicals are described. It is established that most of the synthesized compounds exhibit a high antioxidant activity, possess pronounced hemorheological properties, and influence the blood glucose level.

Synthesis and pharmacological activity of 2-methoxyphenyl-and 2-oxyphenyl-substituted 1-dialkylaminoalkylimidazo[1,2-a]-benzimidazoles

A series of 2-methoxy-and 2-oxyphenyl-1-dialkylaminoalkylimidazo[1,2-a]benzimidazoles have been synthesized and characterized with respect to pharmacological properties. Some of the synthesized compounds exhibit antioxidant, membranotropic, antiaggregant, hemorheological, anticalmodulin, and hypotensive properties, and behave as antagonists of serotonin (5-HT2,3) and purine (P2Y1) receptors. The obtained data show good prospects for the synthesis and screening of biologically active substances in this class of compounds.

Prototropic equilibrium in 1(11)H-2, 3, 4, 5-tetrahydro[1, 3]diazepino[1, 2-a]benzimidazole, synthesis and pharmacological properties of its N-substituted derivatives

Based on the X-ray crystallography and 1H NMR spectroscopy data and quantum chemical studies, it was found that 1(11)H-2, 3, 4, 5-tetrahydro[1, 3]diazepino[1, 2-a]benzimidazole (1) exists almost exclusively in the 1H-prototropic form. To prepare the fixed 11H-diazepinobenzimidazole forms of 1, 1-R-2-(4-chlorobutylamino)benzimidazoles (R = Me, N=CHAr) were synthesized, which underwent thermal cyclization with the formation of a mixture of 11-Rsubstituted diazepine 1 and 1-R-2-(pyrrolidin-1-yl)benzimidazole. Alkylation of diazepine 1 in a neutral medium regioselectively gave 11-R-diazepinobenzimidazoles in high yield. Their 1-substituted isomers were obtained by carrying out this reaction in the system NaH—THF. The N(11)-derivatives of diazepinobenzimidazole 1 were found to inhibit dipeptidyl peptidase 4 (DPP-4), but less actively than a comparator drug sitagliptin. The compounds under study did not exhibit antiglycation action in vitro and virtually did not affect activity of α-glucosidase and glycogen phosphorylase. However, they are characterized by a strong antiaggregant effect, making these derivatives promising for further studies.

Antithrombogenic activity of antioxidant compounds.

Antithrombotic activities of enoxifol, a new antioxidant with antiaggregant activity demonstrated in vitro and in vivo, and antioxidant mexidol were compared on the rat model of arterial thrombosis induced by application of 50% ferric chloride. Acetylsalicylic acid (antiaggregant) served as the reference drug. All drugs exhibited dose-dependent antithrombotic activity. Enoxifol was more effective than mexidol, both drugs being more active than the reference drug (acetylsalicylic acid). Taking into account the pathogenesis of the thrombosis in this experimental model, we can hypothesize that the pronounced antithrombotic effect of enoxifol was due to its antiaggregant and antioxidant activities.

Synthesis and pharmacological activity of 1-dialkyl(alkyl)aminoethyl-2,3-dihydroimidazo[1,2-a]benzimidazoles

In continuation of the investigation of 1-dialkylaminoethyl-2,3-dihydroimidazo[1,2-a]benzimidazoles demonstrating serotoninergic activity, several new substances of this class with 4-substituted piperazines and piperidines as amine moieties were synthesized and tested pharmacologically in vitro. All substances were investigated for antiserotoninergic, antiplatelet, haemorheological, antiarrhythmic, and antioxidant activity.

Synthesis of 1(11)H-2,3,4,5-tetrahydro[1,3]diazepino[1,2-a]benzimidazole starting from benzimidazole-2-sulfonic acid. Intramolecular cyclization of 2-(δ-chlorobutylamino)benzimidazole

The intramolecular cyclization of 2-(δ-chlorobutylamino)benzimidazole (3c) follows the unusual pathway involving the predominant attack on the exocyclic amino group rather than on the much more nucleophilic endocyclic nitrogen atom. This reaction affords 2-pyrrolidinobenzimidazole and 1(11)H-2,3,4,5-tetrahydro[1,3]diazepino[1,2-a]benzimidazole as the major product and the by-product, respectively. The cyclization can be directed exclusively toward the annulation of the diazepine ring only after the acetylation of the amino group of compound 3c. According to the quantum chemical calculations, the unusual regioselectivity of the cyclization of chloramine 3c is associated primarily with a substantially less steric strain and the higher entropy of pyrrolidine transition states compared to diazepine transition states.